In light of the increasing prevalence of obesity in our society, elucidation of novel regulatory pathways that could potentially limit the pathophysiological consequences of obesity is of great importance. Elevated inflammatory cytokines are thought to contribute to insulin resistance and the development of chronic metabolic diseases such as type II diabetes, atherosclerosis and cardiovascular disease in obese individuals (1-3). In obese, insulin resistant subjects, macrophage activation increases release of inflammatory cytokines and there is increased macrophage accumulation in adipose tissue (4-7). Exciting new findings demonstrate a link between the central nervous system and regulation of cytokine release from macrophages. Termed the 'cholinergic anti-inflammatory pathway', the data suggest that the release of acetylcholine from vagal efferent fibers inhibits macrophage activation and the subsequent release of inflammatory cytokines (8-12). My laboratory is one of very few to study the role of the vagus nerve in the regulation of glucose homeostasis in humans (13-15). This proposal will apply our knowledge and expertise of vagal physiology to explore for the first time, the role of the nicotinic acetylcholine receptor in vagally mediated inflammatory responses in human obesity. We will test the hypothesis that pharmacological activation of the Nicotinic Acetylcholine Receptor (NAcR) by nicotine will decrease the elevated circulating inflammatory cytokines in obese, insulin resistant humans. The aim of the project is to determine if activation of nicotinic acetylcholine receptors by nicotine administration decreases markers of inflammation. The exploratory aim will evaluate the effect of nicotine administration on insulin sensitivity and sympathetic nervous system activity (SNS) obese insulin resistant subjects. We will use a within subject, crossover design and administer either transdermal nicotine, a known agonist of the nicotinic acetylcholine receptor 1-7 subunit or co-administer transdermal nicotine and the nicotinic acetylcholine receptor antagonist, mecamylamine. During both conditions, we will measure markers of inflammation: IL-6, TNF-1, TNF-1 receptor 2, resistin and the anti- inflammatory marker IL-10. In addition, we will measure insulin sensitivity using the frequently sampled intravenous glucose tolerance test and SNS activity with heart rate variability and urinary catecholamines. This translational study will investigate a previously unexplored mechanism which may contribute to the inflammatory state associated with human insulin resistance. Findings from this study will provide a scientific basis for future translational studies and elucidate a potential therapeutic target for pharmacological intervention. PUBLIC HEALTH RELEVANCE: Elevated levels of cytokines, proteins associated with inflammation, may be responsible for some of the adverse consequences of metabolic diseases such as obesity, type 2 diabetes, cardiovascular disease and atherosclerosis. This study will investigate a novel regulatory pathway regulating cytokine levels in humans. Positive findings would support future investigations for the development of a new therapeutic target to lower cytokine levels in obese individuals.